Iodinated substituted mercaptoimidazoles



Patented Oct. 6, 1953 UNITED STATES PATENT OFFICE IODINATED SUBSTITUTED MERCAPTO- IMIDAZOLES Charles F. Huebner, Morristown, and Caesar R.

Scholz, Summit, N. J., assignors to Ciba Pharmaceutical Products, Incorporated, Summit, N. J., a corporation of New Jersey No Drawing. Application July 14, 1951, Serial No. 236,862

20 Claims. (Cl. 260-309) wherein R stands for H, lower alkyl or I, X stands for H or I, at least one of R and X being I, R stands for H or lower alkyl, and R stands for alkyl, aryl-methyl, or a radical derived from an a-halogen carboxylic acid.

A further object of the invention is the embodiment of methods for the preparation of the aforesaid iodinated substituted mercapto-imidaz-oles. This further object is realized, according to the invention, whereby iodinated substituted mercapto-imidazoles of the desired character can be prepared by benzylating and then iodinating the corresponding mercapto-imidazole in the presence of alkali to form, for example, the 2- benzylmercapto 1,5 diiodoimidazole. In like manner, the sulfhydryl group may be protected by other groups, for example by treating the mercapto-imidazole with an a-halogen carboxylic acid such as bromoacetic acid, chloroacetic acid, e-bromo-propionic acid and bromo-succinic acid, a lower dialkyl sulfate such as :dimethyl sulfate, a lower diazo alkane such as diazomethane, or a naphthylmethyl halide, such as a-naphthylmethyl bromide, whereby the 2-carboxyalkylmercapto-imidazole or the corresponding alkylmercaptoor naphthylmethylmercapto-imidazole results.

To produce an N-alkylated iodinated mercaptoimidazole, the 2-benzylmercapto-4,5-diiodo-imidazole, for example, may be treated with a lower diazo alkane.

To produce the corresponding monoiodo derivative, the diiodo derivative-for example 4,5- diiodo 2 benzylmercapto-imidazolemay be treated with a molar equivalent of a metal SL111- flte in aqueous alkaline solution. Alternatively,

4-iodo-2-alkylmercapto-imidazole for example can be prepared from 4,5-diiodo-2-mercaptoimidazole by treating the latter with the metal sulfite followed by alkylation of the sulfhydryl radical.

Another type of mono-i-odinated imidazole derivative may be prepared by the iodination of 4-alkyl-2-benzylmercapto-imidazoles, only one iodine being introduced into the molecule.

The various transformations according to this invention are carried out according to the following reaction scheme:

R1 R1 :2: Rahal H024) I I I I HN\ N HN N is LR I 13. lower I R1 R1 l diazo (g (L: 4} 0:0 alkane 2 S03" HG: R l I I l l I -N N H N HN N W o (I: o b -R s-R1 1 ALB 1'3 lAlBlx {B11181 I R I R1 R1 a, et R-N N HN N HN o 0 0 s11 AH AH For debenzylation, when R2: benzyl.) wherein, R, R and R have the previously indicated significances. When benzyl bromide, for

instance, is the R hal reactant, the product is the Z-benzylmercapto derivative. When a halogen carboxylic acid or an alkylating agent is the R .ha1 reactant, the product is the z-carboxyalkylmercapto derivative, rather than the 2-benzylmercapto derivative. When, for instance, a naphthylmethyl chloride is employed, the product is the corresponding derivative. When R is hydrogen in the imidazole subjected to the iodination reaction, the resulting product is a 4,5-diiodo derivative and the char acter of the R has thus been changed during the reaction. r

In the foregoing processes, the reaction with the. benzyl halide or naphthylmethyl halide is naphthylmethylmercapto The N-alkylation is advantageously carried in the case of the 2-benzylmercapto-4,5-diiodo-imidazole, in a lower aliphatic out, particularly alcohol (e. g. methanol, ethanol) or ketone (acetone), using a lower diazo alkane (e; g. diazomethane).

"Debenzylation may be accomplished as described in copending application, Serial No. 236,861, filed July 14, 1951, e. g. by treating the 2-benzylmercapto derivative with anhydrous aluminum bromide at room temperature in a solvent such as benzene, carbon disulfide, carbon tetrachloride and the like. The reaction mixture is then worked up by slowly adding ice, while stirring, to destroy the aluminum complex and to precipitate the debenzylated imidazole. It may be further purified by solution in aqueous alkali followed by precipitation by addition of acetic acid.

The new compounds, when used as X-ray agents, are preferably administered parenterally.

The following examples set forth representative exemplary embodiments of the invention, and these examples are intended to be solely illustrative and not at all limitative. In these examples, the temperatures are given in degrees centigrade. Parts by weight bear the same relation to parts by volume as .do grams to milliliters. Percentages are by weight. All melting points are uncorrected.

Example 1 58 parts by volume of benzyl bromide are added to a suspension of 49 parts by weight of Z-mercapto-imidazole in 300 parts by volume of ethanol. Immediate reaction is evident by a rapid rise in temperature of the mixture. After two hours, by which time the reaction mixture has cooled, an equal volume of ether is added to bring about complete precipitation of Z-benzylmercapto-imidazole hydrobromide which is filtered off. The latter is converted to the free base by dissolving in water and making the solution alkaline with an excess of ammonia. The free base is recrystallized from methanol; it melts at 145-146.

'-'-15 parts by weight of the thus-prepared 2-benzylmercapto-imidazole are suspended in a mixture of 200 parts by volume-of dioxane and a solution of 19 parts by weight of sodium hydroxide in 30 par-ts by volume of water. To the suspension, while stirring, is added a solution of 40wparts by weight of iodine and 40 parts by weight of potassium iodide in 100 parts by volume of water. The addition takes about A2 hour, and is carried out with external cooling in order tomaintain a temperature of about 20-30. After another half. .hour, most of the dioxane is removed by distillation .in vacuo. The resultin reaction mixture is acidified with hydrochloric acid and the solid thoroughly triturated to insure complete decomposition of the sodium salt of the imidazole. The slight excess of iodine remaining is decolorized by the cautious addition of sodium bisulfite. The crystalline 2-benzylmercaptol,5-diiodo-imidazole of the formula thus obtained is filtered and recrystallized from sodium hy- 1 ethanol; it melts at 144-145.

In the foregoing, the benzyl bromide may be replaced by an equivalent quantity of a-naphthylmethyl chloride or bromide whereupon, while otherwise proceeding as described, the corresponding a-naphthylmethyl derivative is obtained.

Example 2 2 parts by weight of 2-benzylmercapto-4,5-diiodo-imidazole are dissolved in 50 parts by volume of warm ethanol, quickly cooled and treated with an excess of etheral diazo-methane. After 2 hours, the solvent is removed by distillation and the residue recrystallized from ethanol; it melts at '73-'74". The product2'-benzylmercapto 4,5 diiodi-l-methyl imidazole-corresponds to the formula By using an equivalentquantity the a-naphthylmethyl derivative of Example 1 in lieu of the 'benzy1mercapto-4,5-diiodo-imidazole, and otherwise proceeding as in the preceding paragraph, the corresponding a-naphthylmethyl derivative is obtained.

Example 3 5 parts by Weight of 2-benzylmercapto4,=5-diiodo-imidazole are refluxed with 5 parts byweig'ht of sodium bisuli-lte in .50 parts by volume of ethanol-water (5: 1) for '12 hours. The solvent is distilled off and the crystalline residue filtered, washed with Water and recrystallized from benzene-petroleum ether to yield 2-benzylmercapto- 4(5)-iodo-imidazole, which melts at 107-110".

The product corresponds to the formula HI lI I -CHzCoHs [The convention 4(5)- or (4) is used in this specification to indicate that the designated substituent may be in either the 4- or 5-position. It will be noted, in this regard, that in the 2- mercapto-imidazoles which are unsubstituted in the 1- or 3-positions, the 4- and fi-positions are interchangeable. Thus, 2-benzylmercapto-4- iodo-imidazole can just as well be 2-benzylmercapto-5-iodo-imidazole.l

Example 4 Example 5 parts by weight of 4,5-diiodo-2-mercaptol-methyl-imidazole and 7 parts by weight of sodium sulfite heptahydrate in 200 parts by volume of water containing 1.5 parts by weight of sodium hydroxide are refluxed for 12 hours. Addition of acetic acid precipitates monoiodo-2- mercapto-l-methyl-imidazole which is recrystallized from ethanol; it melts at 164 (darkening at decomposition). The latter is treated with benzyl bromide according to the procedure described in Example 1 to yield 2-benzylmercaptomonoiodo-l-methyl-imidazole.

[It will be understood that when l-alkyl-imidazoles are prepared, the exact configuration of the substituents in the 4- and S-positions, if these substituents are diiferent, is not known so that it is not possible to assign an exact structure to such compounds. However, it is known that the monoiodo compound prepared by the present example corresponds to one of the formulae I 4Y=CH HsOl T I l and -O H2 C aHs Example 6 15 parts by Weight of 2-mercapto-imidazo1e, 21 parts by weight of bromoacetic acid, and 6 p melting point 170 parts by weight of sodium hydroxide in solution in 150 parts by volume of water are heated for 15 minutes on the steam bat which would permit the crystallization of the formed 2-imidazo1yl-mercaptoacetic acid, melting at -35.4 parts by weight of sodium hydroxide in parts by weight of water are added and to the resulting solution, which is kept at 20-30 by external cooling, is added over one half hour a solution of '73 parts by weight of iodine and '73 parts by weight of potassium iodide in 180 parts by volume of water. After an additional half hour, addition of hydrochloric acid precipitates the crystalline (4,5-diiodo-2- imidazolyl)-mercaptoacetic acid of the formula I i HN N which may be recrystallized from ethanol-water;

(with decomposition).

The same product can be prepared by the reaction of 4,5diiodo-2-mercapto-imidazole with bromoacetic acid in the presence of two molar equivalents of sodium hydroxide as described above. The sodium salt of this acid is freely soluble in water and is of a pH (8.0) suitable for intravenous injection.

By replacing the equivalent quantity -CHCOOH may be obtained, while if bromo-succinic acid is used, the corresponding S-substituted product may be obtained.

Example 7 10.5 parts by volume of benzyl bromide are added to a suspension of 10 parts by weight of 2-mercapto-4(5) "methyl-imidazole in 60 parts by volume of ethanol. After reaction as described in Example 1, the hydrobromide is obtained by precipitation with ether and the benzylmercapto-4( 5) -methyl-imidazole is tained after recrystallization from ethanol; melting point 105-l06.

15 parts by weight of the said 2-benzylmercapto-4 (5) -methy a period of one-half hour while maintaining the temperature between 20 and 30. After another half hour, the reaction mixture is worked up as described in Example 1. The formed crystalline 2 benzylmercapto-5(4)-methyl-imidazole, on recrystallization from ethanol, melts at 157.

Example 8 8.4 parts by volume of benzyl bromide are added to a suspension mercapto-4-propylimidazole in 60 parts by volume of ethanol. After reaction as described in Example 1, the hydrobromide is obtained by precipitation with ether. The non-crystalline free base is iodinated as described in Example '7, except that for 15 parts by weight of the formed 2- benzylmercapto lpropyl-imidazole there are used 7.8 parts by weight of sodium hydroxide in 35 parts by volume of water and 16.4 parts by weight of iodine and 16.4 parts by weight of potassium iodide in 100 parts by volume of water. The iodinated product, 2-benzylmercapto-5-iodo- 4-propyl-imidazole is isolated as described in Example 1; melting point 90-92% The product corresponds to the formula l HN i l L-GHzCaHs wherein R stands for a member selected from the group consisting of hydrogen and lower alkyl, R stands for a member selected from the group consisting of hydrogen, lower alkyl and iodine, at least one of R and X being iodine, and R stand for a member selected from the group consisting of lower alkyl, mononuclear and binuclear carbocyclic arylmethyl radicals, and a radical derived from lower a-halogen carboxylic acid.

2. 2-benzylmercapto-monoiodo-imidazole.

3. 2-benzylmercapto-monoiodo-1-lower alkyl imidazole.

4. 2-benzylmercapto4,5-diiodo-1-lower alkylimidazole.

V '5. 2-benzylmercapto-5M)-iodo-4'(5)lower al kyl-imidazole.

6. 2-benzylmercapto-,5 diiodo-imidazole.

'7. 2-benzylmercapto-4 -iodo-imidazole.

8. 2 benz-ylmercapto 4,5 diiodo 1 methyl-imidazole.

9. 2 benzylmercapto 5 iodo 4 methylimidazole.

10. (4,5 diiodo 2 imidazolyl) mercaptoacetic acid.

11. A process for the production of an iodinated substituted mercapto irnidazole which includes the step of reacting a 2mercapto-l-R -imidazole, wherein R stands for a member selected from the group consisting of hydrogen, lower alkyl and iodine, with the group consisting of mononuclear and binuclear carbocyclic arylmethyl halides, lower ahalogen carboxylic acids, lower dialkyl sulfates and lower diazo alkanes, the reaction being carried out in a neutral oxygenated polar solvent in the case of the arylmethyl halides and the lower diazo alkanes and in aqueous alkaline soluof parts by weight of 2- a member selected from tion in the case of the lower a-halogen carboxylic acids and the lower dialkyl sulfates.

12. A process for the production of an iodinated substituted mercapto-imidazole which includes the step of reacting a 2-mercaptol-R imidazole, wherein R stands for a member selected from the group consisting of hydrogen, lower alkyl and iodine, with benzyl bromide in a neutral oxygenated polar solvent, whereby the 2-benzyl-mercapto-4-R -imidazole is produced.

13. The process for the production of an i0- dinated substituted mercapto-imidazole which includes the step of reacting a 2-mercaptoi-R imidazole, wherein R stands for a member selected from the group consisting of hydrogen, lower alkyl and iodine, with a member selected from the group consisting of mononuclear and binuclear carbocyclic arylmethyl halides, lower a-halogen carboxylic acids, lower dialkyl sulfates and lower diazo alkanes, the reaction being carried out in a neutral oxygenated polar solvent in the case of the arylmethyl halides and the lower diazo alkanes and in aqueous alkaline solution in the case of the lower a-halogen carboxylic acids and the lower dialkyi sulfates. and reacting the product with iodine in a solvent containing alkaline OH ions.

14. A process for the production of an iodine-ted substituted mercapto-imidazole which includes the step of reacting a 2-mercapto-4-R imidazole, wherein R stands for a member selected from the group consisting of hydrogen, lower alkyl and iodine, with benzyl bromide in a neutral oxygenated polar solvent, whereby the 2-benzyl-mercapto-4-R -imidazole is produced, and reacting the product with iodine in a solvent containing alkaline OH ions.

15. A process for the production of 2-benzylmercapto-l,5diiodo-imidazole which comprises reacting Z-mercapto-imidazole with benzyl bromide in a neutral oxygenated polar solvent, and reacting the resultant Q-benzylmercapto-imidazole with iodine in a solvent containing alkaline OH ions, whereby the l,5diiodo derivative results.

16. A process for the production of 2 -benzylmercapto-monoiodo imidazole which comprises reacting Z-mercapto-i-midazoie with benzyl bromide in a neutral oxygenated polar solvent, reacting the resultant2henzylmercapto-imidazole with iodine in a solvent containing alkaline O-l-I ions, whereby the 2-benzylmercapto-l,5-diiodo-' imidazole results, and de-iodinating the latter to the corresponding monoiodo compound with the aid of a metal sulfite.

17. A process for the production of (4,5-di-iodo- Z-imidazolyl)-mercaptoacetic acid which comprises reacting 4,5-diiodo2-1nercapto-imidazole with bromoacetic acid i n aqueous alkaline soluion.

18. A process for the production of (4,5-diiodo- Z-imidazolyl)-mercaptoacetic acid which comprises reacting 2;mercapto-imidazole with bromoacetic acid in aqueous alkaline solution, and then iodinating the resultant 2-imidazolyl-mercaptoacetic acid by reacting it with iodine in a solvent containing alkaline OH ions.

19. A process for the production of Z-benzylmercapto-5io=:loi-rnethyl-irnidazole which comprises reacting 1-mercaptol-methyl-imidazole with benzyl bromide in a neutral oxygenated polar solvent, and then iodinating the resultant 2- benzylmercaptol-methyl-imidazole by reacting it with iodine ina solvent containing alkaline OI-Iions.

20. A process for the production of 2-benzy1- mercapto-5-iodo-4-propyl imidazole which comprises reacting 1-mercapto-4-propyl-imidazole with benzyl bromide in a neutral oxygenated polar solvent, and then iodinating the resultant 2- benzylmercapto-4-propyl-imidazole by reacting it with iodine in a solvent containing alkaline OH ions.

CHARLES F. HUEBNER. CAESAR R. SCHOLZ.

References Cited in the file of this patent Pauley: Ber-Dent. Chem. 43, pp. 2243-2261 (1910).

Pauley et al.: J. Prokt. Chem. 118, pp. 33-47 (1928).

Astwood et aL: Endocrinology, vol. 37, 1945, pp. 456-481.

Stanley et al.: Endocrinology, Vol. 44 (1949). page 588.

Stanley et 9.1.: Endocrinology, vol. 41 (1947). pp. 66-84. 

1. AN IODINATED SUBSTITUTED MERCAPTO-IMIDAZOLE WHICH CORRESPONDS TO THE FORMULA 